Bicyclo[3.3.1]nonyl-benzamide

ABSTRACT

Compounds of the formula (I) and pharmaceutically acceptable salts thereof: ##STR1## wherein: X is oxygen or sulphur; 
     R 1  is a C 1-6  alkoxy or C 1-6  alkylthio group; 
     R 2  and R 3  are the same or different and are hydrogen, halogen, CF 3 , C 1-7  acyl, C 1-7  acylamino or amino, aminocarbonyl or aminosulphonyl optionally substituted by one or two C 1-6  alkyl groups, C 1-6  alkylsulphonyl, C 1-6  alkylsulphinyl, C 1-6  alkoxy, C 1-6  alkylthio, hydroxy or nitro or R 1  and R 2  taken together are methylenedioxy or ethylenedioxy in which case R 3  is any one of the groups given for R 2  and R 3  above; 
     R 4  is C 1-7  alkyl or a group --(CH 2 ) s  R 5  where s is 0 to 2 and R 5  is a C 3-8  cycloalkyl group, or a group --(CH 2 ) t  R 6  where t is 1 or 2 and R 6  is a phenyl group optionally substituted by one or two substituents selected from C 1-6  alkyl, C 1-4  alkoxy, trifluoromethyl and halogen, or a thienyl group; and 
     n is 0 to 2; and there are at least two carbon atoms between the benzamide and heterogranatane ring nitrogen atoms, having useful pharmacological activity, pharmaceutical compositions contain them and process for their preparation.

This invention relates to novel substituted benzamides having usefulpharmacological properties, to pharmaceutical compositions containingthem, and to a process for their preparation.

N-(2-Diethylaminoethyl)-2-methoxy-4-amino-5-chlorobenzamide,1-ethyl-2(2-methoxy-5-sulphamoylbenzamidomethyl)pyrrolidine andN-[4'-(1"-benzyl)-piperidyl]-2-methoxy-4-amino-5-chlorobenzamide arewell known compounds having useful pharmacological activity such as theability to regulate the gastro-intestinal function, anti-emetic activityand CNS activity.

It has now been found that a certain structurally distinct class ofsubstituted benzamides also has useful pharmacological activity, inparticular dopamine antagonist activity.

Accordingly the present invention provides compounds of the formula (I)and pharmaceutically acceptable salts thereof: ##STR2## wherein:

X is oxygen or sulphur;

R₁ is a C₁₋₆ alkoxy or C₁₋₆ alkylthio group;

R₂ and R₃ are the same or different and are hydrogen, halogen, CF₃, C₁₋₇acyl, C₁₋₇ acylamino or amino, aminocarbonyl or aminosulphonyloptionally substituted by one or two C₁₋₆ alkyl groups, C₁₋₆alkylsulphonyl, C₁₋₆ alkylsulphinyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio,hydroxy or nitro or R₁ and R₂ taken together are methylenedioxy orethylenedioxy in which case R₃ is any one of the groups given for R₂ andR₃ above;

R₄ is C₁₋₇ alkyl or a group --(CH₂)_(s) R₅ where s is 0 to 2 and R₅ is aC₃₋₈ cycloalkyl group, or a group --(CH₂)_(t) R₆ where t is 1 or 2 andR₆ is a phenyl group optionally substituted by one or two substituentsselected from C₁₋₆ alkyl, C₁₋₄ alkoxy, trifluoromethyl and halogen, or athienyl group; and

n is 0 to 2; and there are at least two carbon atoms between thebenzamide and heterogranatane ring nitrogen atoms.

Suitable examples of the group R₁ include methoxy, ethoxy and n- andiso-propoxy, methylthio, ethylthio, and n- and iso-propylthio.Preferably R₁ is a methoxy group.

Suitable examples of the groups R₂ and R₃ include the following groups:hydrogen, chlorine, bromine, amino, C₁₋₄ alkanoylamino such asformylamino, acetylamino, propionylamino, n- and iso-butyrylamino,aminosulphonyl, and amino and aminosulphonyl substituted by one or twomethyl, ethyl, n- or iso-propyl, n-, sec- or tert-butyl groups, nitro,methoxy, ethoxy, n- and iso- propoxy, methylthio, ethylthio, n andiso-propylthio, and hydroxy.

When R₂ and R₃ are other than hydroxy, C₁₋₆ alkoxy or C₁₋₆ alkylthio, itis generally preferred than R₂ is in the 4-position relative to theheterogranatyl (alkyl) aminocarbonyl side chain for greater activity inthe resultant compound of the formula (I). For the same reason it isgenerally preferred that R₃ is in the 5-position relative to the sameacylamino side chain. When one of R₂ and R₃ is C₁₋₆ alkoxy, it ispreferably methoxy and the other is hydrogen.

Particularly preferred R₂ groups include 4-amino and 4-(acylated amino),especially 4-acetylamino as defined. Preferably R₂ is 4-amino or4-acetylamino. Particularly preferred R₃ groups include 5-halo, such as5-chloro.

Alternatively very suitably R₂ is hydrogen, amino or acylated amino, andR₃ is C₁₋₆ alkylsulphonyl, C₁₋₆ alkylsulphinyl, or aminosulphonyloptionally substituted by one or two C₁₋₆ alkyl groups. In such cases,as above preferably R₂ is in the 4-position and R₃ is in the 5-position;and preferred examples of R₂ include hydrogen and of R₃ includemethylsulphonyl, methylsulphinyl and aminosulphonyl.

When R₁ and R₂ taken together are methylenedioxy or ethylenedioxy R₁ andR₂ are preferably ethylenedioxy.

Suitable examples of R₄ when C₁₋₇ alkyl include methyl, ethyl, n- andiso- and n, sec- and tert-butyl. Within C₁₋₇ alkyl, C₅₋₇ alkyl are ofinterest and suitable examples thereof include n-pentyl, n-hexyl andn-heptyl and 3-methylbutyl.

When R₄ is a group --(CH₂)_(s) R₅ as defined, suitable examples of R₆include C₅₋₈ cycloalkyl, preferably cyclohexyl. s is preferably 1.

When R₄ is a group --(CH₂)_(t) R₆ as defined, t is preferably 1.

When R₆ is optionally substituted phenyl as defined above, suitableexamples of such optional phenyl substituents include methyl, ethyl, n-and iso- propyl, n-, sec, and tert-butyl; methoxy, ethoxy, n- andisopropoxy; CF₃, fluoro, chloro or bromo. One preferred R₆ whenoptionally substituted phenyl is unsubstituted; another is 4-tolyl.

When R₆ is thienyl it may be 2- or 3-thienyl, generally 2-thienyl.

R₄ is preferably benzyl optionally substituted as hereinbefore defined,or 2-thienylmethyl, also called 2-thenyl. Optionally substituted benzylis preferred, particularly benzyl and 4-methylbenzyl.

n is preferably 0.

X is most suitably oxygen.

Often the amide and heterogranatane nitrogen atoms, which are in thesame side chain, are separated by 2 or 3, carbon atoms, most preferably3.

In such most preferable cases the CONH(CH₂)_(n) - moiety is in anequatorial orientation to the heterogranatane ring.

The pharmaceutically acceptable salts of the compound of the formula (I)include acid addition salts with conventional acids such ashydrochloric, hydrobromic, phosphoric, sulphuric, citric, tartaric,lactic and acetic acid.

The pharmaceutically acceptable salts of the compounds of the formula(I) also include quaternary ammonium salts. Examples of such saltsinclude such compounds quaternised by compounds such as R₇ - Y whereinR₇ is C₁₋₆ alkyl, phenyl-C₁₋₆ alkyl or C₅₋₇ cycloalkyl, and Y is aradical corresponding to an anion of an acid. Suitable examples of R₇include methyl, ethyl and n- and iso-propyl; and benzyl and phenylethyl.Suitable examples of Y include the halides such as chloride, bromide andiodide.

Examples of pharmaceutically acceptable salts also include internalsalts such as N-oxides.

The compounds of the formula (I) may also form hydrates and theinvention extends to such hydrates.

A group of compounds within those of formula (I) consists of thosewherein:

R₁ is C₁₋₆ alkoxy;

R₂ and R₃ are the same or different and are hydrogen, halogen,trifluoromethyl, C₁₋₇ acyl, C₁₋₇ acylamino, or amino, aminocarbonyl oraminosulphonyl optionally substituted by one or two C₁₋₆ alkyl groups;C₁₋₆ alkylsulphonyl, C₁₋₆ alkysulphinyl or nitro; or

R₁ and R₂ taken together are methylenedioxy or ethylenedioxy, in whichcase R₃ is any one of the groups given for R₁ and R₂ above;

R₄ is C₁₋₇ alkyl or a group --(CH₂)_(s) R₅ where s is 0 to 2 and R₅ is aC₃₋₈ cycloalkyl group, or a group --(CH₂)_(t) R₆ where t is 1 or 2 andR₆ is a phenyl group optionally substituted by one or two substituentsselected from C₁₋₆ alkyl, C₁₋₆ alkoxy, trifluoromethyl and halogen;

X is oxygen or sulphur;

n is 0, 1 or 2; and there are at least two carbon atoms between thebenzamide and side-chain nitrogen atoms.

From the aforesaid it will be seen that suitably the moiety of formula(II): ##STR3## in a compound of the formula (I) will have the structure(III): ##STR4## wherein R₉ is hydrogen or C₁₋₄ alkanoyl.

A preferred group of compounds within those of formula (I), are those offormula (IV), and pharmaceutically acceptable salts thereof: ##STR5##wherein:

X, R₄ and R₉ are as defined in formulae (I) and (III).

Preferably the moiety of formula (II) is at the 7-position (standardnumbering).

Suitable and preferred examples of R₄ in formula (IV) include thoselisted under formula (I) for R₄. Particularly preferred examples of R₄include benzyl optionally substituted in the phenyl ring as definedunder formula (I). Unsubstituted benzyl is an especially preferred R₄.

Preferably R₉ is hydrogen, formyl or acetyl.

A sub-group of compounds within those of formula (IV) are those of theformula (V): ##STR6## wherein

R¹ ₄ is C₅₋₇ alkyl, and R₉ is as hereinbefore defined.

Suitable examples of R¹ ₄ are as so described for R₄ C₅₋₇ alkyl underformula (I). R₉ is preferably hydrogen, formyl or acetyl.

It is preferred that the CONH moiety is in the β-orientation to theoxagranatane ring, that is as follows: ##STR7##

(The 6α and 6β orientations are also depicted.)

A particularly preferred sub-group of compounds within those of formula(IV) are those of the formula (VI): ##STR8## wherein R² ₄ is a group--(CH₂)_(t) R¹ ₆ wherein t is 1 or 2 and R¹ ₆ is optionally substitutedphenyl as defined in formula (I); cyclohexylmethyl; or 2-thienylmethyl,and R₉ is as hereinbefore defined.

Suitable and preferred R² ₄ are as so described for the corresponding R₄groups under formula (I).

R² ₄ benzyl is one especially preferred value.

It is preferred that the CONH moiety is in the β-orientation to theoxagranatane ring.

A sub-group of compounds within those of the formula (IV) of interestare those of the formula (VII): ##STR9## wherein:

R¹ ₄ and R₉ are as defined in formula (V).

Suitable and preferred R¹ ₄ and R₉ are as described under formula (V).

It is preferred that the CONH moiety is in the β-orientation to thethiagranatane ring, the β-orientation being the same as in theoxagranatane hereinbefore depicted.

Another sub-group of compounds within those of the formula (IV) ofinterest are those of the formula (VIII): ##STR10## wherein:

R² ₄ and R₉ are as defined in formula (VI).

Suitable and preferred examples of R² ₄ and R₉ are as described underformula (VI).

It is preferred that the CONH moiety is in the β-orientation to thethiagranatane ring.

A second group of compounds within those of the formula (I) which is ofinterest is of the formula (IX): ##STR11## wherein:

R¹ ₁ is C₁₋₆ alkoxy;

R¹ ₂ and R¹ ₃ are the same or different and are hydrogen, aminosulphonyloptionally substituted by one or two C₁₋₆ alkyl groups, C₁₋₆alkylsulphonyl, C₁₋₆ alkylsulphinyl, C₁₋₆ alkoxy or hydroxy or

R¹ ₁ and R¹ ₂ taken together are methylenedioxy or ethylenedioxy, inwhich case R¹ ₃ is any one of the groups given above for R¹ ₂ and R¹ ₂ ;and

X and R² ₄ are as defined in formula (VI).

It is preferrred that the CONH moiety is in the β-orientation to theheterogranatane ring.

More suitably R¹ ₁ is methoxy, or together with R¹ ₂ is ethylenedioxy.

R¹ ₂ is preferably hydrogen or methoxy, and R¹ ₃ and R¹ ₁ are thenpreferably both methoxy.

The 2,3-dimethoxy and 2,4,5-trimethoxy nuclei (with respect to --CONH--taken as 1) are particularly preferred.

Suitable and preferred R² ₄ are as so described under formula (VI).

A sub-group of compounds within those of formula (IX) is of the formula(X): ##STR12## wherein:

R² ₃ is aminosulphonyl optionally substituted by one or two C₁₋₆ alkylgroups or C₁₋₆ alkylsulphonyl or C₁₋₆ alkylsulphinyl and X and R² ₄ areas hereinbefore defined.

R² ₃ is preferably aminosulphonyl or methylsulphonyl, in particular5-aminosulphonyl or 5-methylsulphonyl (with respect to the aminocarbonylside chain taken as 1).

Suitable and preferred R² ₄ are as so described under formula (VI).

A second sub-group of compounds within those of formula (IX) are thoseof the formula (XI): ##STR13## wherein:

X, R¹ ₁ and R² ₄ are as defined in formula (IX);

R² ₂ and R³ ₃ are the same or different and are C₁₋₆ alkoxy or hydrogen;or

R¹ ₁ and R² ₂ taken together are methylenedioxy or ethylenedioxy, inwhich case R³ ₃ is any one of the groups given above for R² ₂ and R³ ₃.

Suitable and preferred R¹ ₁, R² ₂, R³ ₃ and R² ₄ are as so describedunder formula (IX) for R¹ ₁, R¹ ₂, R¹ ₃ and R² ₄.

From the aforesaid it will also be seen that a third group of compoundswithin formula (I) of interest are those of the formula (XII): ##STR14##wherein:

n' is 1 or 2 and the remaining variables are as defined in formula (I).

Preferably n is 1.

Suitable and preferred examples of R₄ include those listed hereinbeforefor R₄.

A fourth group of compounds within formula (I) of interest are those ofthe formula (XIII): ##STR15## wherein:

n' is 1 or 2 and X, R¹ ₁, R¹ ₂, R¹ ₃ and R² ₄ are as defined in formula(IX).

Preferably n' is 1.

Suitable and preferred R¹ ₁, R¹ ₂, R¹ ₃ and R² ₄ are as so describedunder formula (IX).

Particularly suitable examples of the compounds of the present inventioninclude those of the Examples hereinafter.

It will of course be realised that the compounds of the formula (I) havechiral or prochiral centres, and thus are capable of existing in anumber of stereoisomeric forms. The invention extends to each of thesestereoisomeric forms, and to mixtures thereof (including racemates). Thedifferent stereoisomeric forms may be separated one from the other bythe usual methods, or any given isomer may be obtained by stereospecificor asymmetric synthesis.

The invention also provides a process for the preparation of a compoundof the formula (I), which process comprises reacting an acid of theformula (XIV): ##STR16## or a reactive derivative thereof, with acompound of formula (XV): ##STR17## wherein:

the variable groups are as defined in formula (I); and thereafter ifdesired or necessary converting a group R₂ or R₃ in the thus formedcompound to another group R₂ or R₃ respectively; converting R₄ whenhydrogen to another R₄ ; and optionally forming a pharmaceuticallyacceptable salt of the resultant compound of the formula (I).

`Reactive derivative` when used herein means a derivative of thecompound (XIV) which can be reacted with the compound (XV) to form anamido linkage between the acid group of the compound (XIV) and the aminogroup of the compound of the formula (XV).

Often this reactive derivative will be the acid halide, such as the acidchloride, of the acid (XIV). In such cases, the reaction will normallybe carried out in an inert solvent preferably in the presence of an acidacceptor. The inert solvent can be any solvent inert to both reactants,such as benzene, toluene, diethyl ether or the like. The acid acceptoris suitably an organic base such as a tertiary amine e.g. triethylamine,trimethylamine, pyridine or picoline, or an inorganic acid acceptor,such as calcium carbonate, sodium carbonate, potassium carbonate or thelike. It should also be noted that it is possible to use certain acidacceptors as the inert solvent, for example organic bases.

These reactions may be carried out at any non-extreme temperature suchas -10°-100° C. and more suitably 0°-80° C. The higher reactiontemperatures are employed with less active acids of the formula (XIV)whereas the lower temperatures are employed with the more reactive acidsof the formula (XIV).

Another useful reactive derivative of the acid (XIV) that may be used isa highly activated ester, such as the pentachlorophenyl ester, whenambient temperatures may be used. The reaction is generally effected inan inert polar solvent, such as dimethylformamide.

The reaction may also be carried out by forming an anhydride of the acid(XIV) in the usual manner, and reacting that with the compound (XV);normally a conventional mixed anhydride will be used; or by reacting theacid (XIV) and the compound (XV) in the presence of a dehydratingcatalyst such as a carbodiimide, for example dicyclohexylcarbodiimide.

The intermediates of the formulae (XIV) and (XV) are either knowncompounds or can be prepared by analogous processes to known compounds.

It will be realised that in the compound of the formula (I) the--CO--NH--(CH₂)_(n) -- linkage may have an α or β orientation withrespect to the ring of the bicyclic moiety to which it is attached. Amixture of α and β isomers of the compound of the formula (I) may besynthesised non-stereospecifically and the desired isomer separatedconventionally therefrom, e.g. by chromatography; or alternatively the αor β isomer may if desired be synthesized from the corresponding α or βform of the compound of the formula (XV).

Synthesis from the corresponding α or β isomer of compound of theformula (XV) is in general preferred.

The α or β form of the compound of the formula (XV) may if desired byprepared by known stereospecific processes, such as those leading to theα or β isomers of the compound of the formula (XV) depicted in theSchemes.

The precursor of the compound of the formula (XV) may bestereospecifically synthesised, such as the azide depicted in theSchemes, and then converted to the corresponding desired isomer of thecompound of the formula (XV) under non-stereospecific conditions withretention of configuration. Alternatively, the precursor may itself haveno asymmetric or prochiral centre at the relevant position, such as theoximes of Description 3 but be converted under stereospecific conditionsto the desired isomer of the compound of the formula (XV).

Alternatively, a mixture of the α and β isomers of the compound of theformula (XV) may be synthesised non-stereospecifically and the desiredisomer separated conventionally therefrom e.g. by chromatography.However, in this case it is generally more convenient to react themixture to give a mixture of α and β isomers of the compound of theformula (I) and to separate these if desired as hereinbefore described.

The following Scheme 1 illustrates stereospecific and non-stereospecificsynthetic routes to intermediates of the formula (XV) wherein n is 0.

It is believed that the compounds of the formula (XV) are novel and assuch form an aspect of the present invention. ##STR18## The followingScheme 2 illustrates preparative routes to intermediates of the formula(XV) wherein n is 1 or 2. ##STR19##

The acid addition salts of compounds of the formula (I) may be preparedin entirely conventional manner by reacting a compound of the formula(I) in base form with the chosen acid.

The quaternary ammonium salts of the compounds of the formula (I) may beprepared in conventional manner for such salts, such as by reaction ofthe chosen compound of the formula (I) with a compound R₇ Y as defined.This reaction is suitably carried out in an appropriate solvent such asacetone, methanol, ethanol, dimethylformamide and the like, at ambientor raised temperature and pressure.

The nitrogen atom of the heterogranatane may also form an N-oxide togive an internal N-oxide salt of the compound of the formula (I). TheN-oxides may be prepared in conventional manner such as by reaction ofthe chosen compound of the formula (I) with an organic per-acid, such asm-chloroperbenzoic acid. This reaction is suitably carried out atbelow-ambient temperature in an organic solvent, preferably achlorinated hydrocarbon solvent.

The skilled man will appreciate that the choice or necessity ofconversion of groups R₂ and/or R₃ to other groups R₂ and/or R₃ will bedictated by the nature and position of substituents R₁, R₂ and R₃.

It will be apparent that compounds of the formula (I) containing an R₂,R₃ or R₄ group which is convertible to another R₂, R₃ or R₄ group areuseful intermediates, and as such form an important aspect of theinvention.

By way of example of such conversions, the compounds of the formula (I)wherein R₂ or R₃ is a nitro group may be prepared via the nitration ofthe corresponding intermediate product wherein R₂ or R₃ is a hydrogenatom.

A particularly suitable nitrating agent for use in this process isfuming nitric acid in the presence of sulphuric acid. In general thereagent is added to a solution of the intermediate wherein R₂ or R₃ ishydrogen, in solution in an organic solvent such as acetic acid.Normally the reaction is carried out at or below ambient temperature,for example 0°-30° C. and more suitably at about 5°-20° C., subject tothe reaction medium remaining fluid.

The nitro compound may be obtained from the reaction mixture by suchconventional means as neutralisation followed by extraction into a waterimmiscible organic solvent such as ethyl acetate or dichloromethane fromwhich it may be recovered by evaporation. If desired the nitro compoundmay be purified by chromatography or by recrystallisation of the freebase or an acid addition salt thereof.

An optional process step provided by this invention in the preparationof the compounds of the formula (I) wherein R₂ or R₃ is an amino groupcomprises the reduction of a corresponding intermediate wherein R₂ or R₃is a nitro group.

The reduction of the intermediates wherein R₂ or R₃ is a nitro group maybe effected with reagents known to be suitable for reducing nitroanisoleto aminoanisole. A suitable reagent for this reduction is stannouschloride in hydrochloric acid or in mixtures of hydrochloric and aceticacid. The desired amino compound may be obtained from the reactionmixture by respectively neutralisation followed by extraction into awater immiscible solvent such as ethyl acetate from which it may berecovered by evaporation of the solvent.

Another suitable method is catalytic hydrogenation at atmosphericpressure in polar solvent such as ethanol. Transition metal catalystssuch as Raney nickel are often used. The desired compound may beobtained from the reaction mixture by filtration and evaporation todryness.

The initial crude product in both cases may be purified bychromatography or crystallisation or by forming an acid addition saltwhich may be recrystallised.

In general however, it is more convenient to prepare a compound of theformula (I) wherein R₂ or R₃ is an amino group from the correspondingC₁₋₇ acylamino acid or its reactive derivative, and to deacylate thecompound of the formula (I) so formed.

Those compounds of the invention wherein R₂ or R₃ is a C₁₋₇ acylaminogroup may be prepared from the corresponding intermediate wherein R₂ orR₃ is an amino group by reaction with an acylating derivative, such aspreviously described as a suitable acylating derivative, e.g. of theacid of the formula (XIV). The reaction may proceed as described for thereaction of the compounds of the formula (XIV) and (XV). For an R₂ /R₃formamido group acylation may be effect with the free acid.

This invention thus also provides an optional process for thepreparation of a compound of the formula (I) wherein R₂ or R₃ is anamino group which process comprises the deacylation of a correspondingintermediate wherein R₂ or R₃ is a C₁₋₇ acylamino group.

Generally the hydrolysis reaction may be effected by treatment with abase such as an alkali metal hydroxide.

Also a compound of the formula (I) wherein R₂ or R₃ is halogen may beprepared by a conventional halogenation of the correspondingintermediate wherein the said R₂ or R₃ is hydrogen.

Similarly the compounds wherein R₂ or R₃ is C₁₋₆ alkylthio or C₁₋₆alkylsulphinyl may be oxidised to the corresponding compounds wherein R₂or R₃ is C₁₋₆ alkylsulphinyl or C₁₋₆ alkylsulphonyl respectively.

These oxidations may conveniently be carried out conventionally at belowambient temperatures using an organic peracid in a non-aqueous inertreaction medium preferably a chlorinated hydrocarbon solvent, forexample using 3-chloroperbenzoic acid, or using a water solubleinorganic strong oxidant, such as an alkali metal permanganate orhydrogen peroxide in aqueous solution.

It will be appreciated by the skilled man that, depending on the otherspecific substituents in the compound of the formula (I), such anoxidation on a compound of the formula (I) may also form the N-oxide ofthe bicyclic moiety therein.

Given the specific substitution desired and having been decided whetherthe compound or its N-oxide is required, the skilled man will readilyascertain whether such R₂ /R₃ interconversion is desirable. In generalit is preferred to effect the oxidation in the intermediate of formula(XIV) before coupling.

It will be appreciated that, when R₄ in the compound of the formula (I)is R₅, which is optionally substituted benzyl as hereinbefore defined,R₄ may be replaced by another group R₄.

Such R₅ benzyl groups may be removed for example when R₂ or R₃ is nothalogen by conventional transition metal catalysed hydrogenolysis togive compounds of the formula (XVI): ##STR20## wherein the variablegroups are as defined in formula (I).

This invention also provides an optional process step in the preparationof a compound of the formula (I) which comprises the reaction of acorresponding compound of the formula (XVI) as hereinbefore defined witha compound QR₄ wherein R₄ is as defined in formula (I) and Q is a groupor atom readily displaced by a nucleophile, and optionally forming apharmaceutically acceptable salt of the resulting compound of theformula (I).

Suitable values for Q include Cl, Br, I, OSO₂ CH₃ or OSO₂ C₆ H₄ pCH₃.

Favoured values for Q include Cl, Br and I.

Particularly suitably the compound QR₄ is a benzyl halide such as benzylbromide or benzyl chloride.

The reaction may be carried out under conventional alkylation conditionsfor example in an inert solvent such as dimethylformamide in thepresence of an acid acceptor such as potassium carbonate. Generally thereaction is carried out at a non-extreme temperature such as at ambientor at a slightly elevated temperature.

However, it is generally more convenient to interconvert R₄ in thecompound of the formula (XV) before coupling with the compound of theformula (XIV) or its derivative. Such interconversions are effectedconveniently under the above conditions. It is desirable to protect theamine function with a group readily removeable by acidolysis such as aC₂₋₇ alkanoyl group before R₄ interconversion.

It will be appreciated that, when R₂ or R₃ are converted to other R₂ orR₃ and R₈ being hydrogen is converted to R₄, then these conversions maytake place in any desired or necessary order.

As hereinbefore stated, the compounds of the formula (I) are dopamineantagonists.

Depending on their balance between peripheral and central action, thecompounds of the formula (I) may be used in the treatment of disordersrelated to impaired gastro-intestinal motility, such as retarded gastricemptying, dyspepsia, flatulence, oesophagal reflux, peptic ulcer andemesis, and/or in the treatment of disorders of the central nervoussystem, such as psychosis.

All the compounds of the formula (I) may be used in the treatment ofemesis.

Examples of compounds of the formula (I) which are of particularinterest for their CNS activity, in particular anti-pyschotic activity,are those wherein R₄ is R¹ ₄ or R² ₄ as defined, preferably R² ₄, inparticular optionally substituted benzyl.

Examples of compounds of more interest for their beneficial effect ongastric motility are the quaternary ammonium salts of the compounds ofthe formula (I).

The invention also provides a pharmaceutical composition comprising acompound of the formula (I), or a hydrate or a pharmaceuticallyacceptable salt thereof, together with a pharmaceutically acceptablecarrier. Such compositions may be adapted for oral or parenteraladministration, and as such may be in the form of tablets, capsules,oral liquid preparations, powders, granules, lozenges, reconstitutablepowders, injectable and infusable solutions or suspensions and the like;the compositions may also be in the form of suppositories and the like.Normally, orally administrable compositions are preferred.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, fillers, tabletting lubricants, disintegrants, andacceptable wetting agents and the like. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups, or elixirs, or may bepresented in a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, emulsifying agents,non-aqueous vehicles (which may include edible oils), preservatives, andif desired conventional flavouring or colouring agents, and the like.

For parenteral administration. fluid unit dosage forms are preparedutilizing the compound of the formula (I) and a sterile vehicle. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved for injection and filter sterilized beforefilling into a suitable vial or ampoule and sealing. Advantageously,adjuvants such as a local anaesthetic, preservatives and bufferingagents can be dissolved in the vehicle. Parenteral suspensions areprepared in substantially the same manner except that the compound issuspended in the vehicle instead of being dissolved and sterilized byexposure to ethylene oxide before suspending in the sterile vehicle.Advantageously, a surfactant or wetting agent is included in thecomposition to facilitate uniform distribution of the compound.

As is common practice, the compositions will usually be accompanied bywritten or printed directions for use in the medical treatmentconcerned.

It will of course be realised that the precise dosage used in thetreatment of any of the hereinbefore described disorders will depend onthe actual compound of the formula (I) used, and also on other factorssuch as the seriousness of the disorder being treated.

The invention further provides a method of treatment of maladies inhumans comprising the administration of an effective amount of acompound of the formula (I) or a pharmaceutically acceptable saltthereof. The "effective amount" will depend in the usual way on a numberof factors such as the nature and severity of the malady to be treated,the weight of the sufferer, and the actual compound used.

However by way of illustration, unit doses will suitably contain 0.1 to20 mgs of the compound of formula (I), for example 0.5 to 10 mgs.

Again by way of illustration, such unit doses will suitably beadministered more than one a day, for example 2, 3, 4, 5 or 6 times aday, in such a way that the total daily dose is suitably in the range0.01 to 10 mg/kg per day.

Compounds of the formula (I) have the ability to potentiate the effectof conventional analgesics in migraine treatment when administeredconcurrently with the analgesic.

Thus the invention provides a pharmaceutical composition comprising acompound of the formula (I) and an analgesic.

The compound of the formula (I) and the analgesic, such as aspirin orparacetamol, will be present in the composition in amounts generallysimilar to their usual effective dose.

The composition can be a combination product, for example a tablet orcapsule containing both a compound of the formula (I) and an analgesicfor oral administration, or a twin pack comprising the two activeingredients made up for separate administration.

The invention accordingly provides a method of treatment of migrainecomprising the administration to the sufferer of a compound of theformula (I) and an analgesic.

The following Examples illustrate the preparation of the compounds offormula (I) and the following Descriptions illustrate the preparation ofintermediates thereto.

DESCRIPTION 1A 9-Benzyl-9-aza-3-oxabicyclo(3,3,1)-nonan-7-one (D1)##STR21##

Oxydiacetaldehyde bis dimethylacetal (11.7 g, 60.3 mmole) was stirredand refluxed with a solution of 3 ml glacial acetic acid and 12 ml waterfor a period of 2 hours. This was then allowed to cool and the solutionwas diluted with 150 ml of a buffer solution made from citricacid/disodium hydrogen phosphate. A solution of benzylaminehydrochloride (made from 11.9 ml benzylamine and 9 ml concentratedhydrochloric acid) was then added followed by portionwise addition ofacetone dicarboxylic acid (17.55 g, 120 mmole). The pH of the resultingsolution was adjusted to 4, and this was allowed to stir for 36 hourswith occasional addition of citric acid to maintain the pH.

At the end of this period the solution was made strongly acidic withhydrochloric acid and this was extracted with several portions of ether(which were discarded). The solution was then basified with aqueoussodium hydroxide and extracted with dichloromethane (4×300 ml).Evaporation of the organic extracts gave a brown oil sludge which wasrecrystallized from dichloromethane to give the desired ketone as anoff-white solid (2.55 g, 18%).

DESCRIPTION 1B 9-Benzyl-9-aza-3-thiabicyclo(3,3,1)nonan-7-one (D2)

Thiadiacetaldehyde bis-dimethylacetal (23.1 g) was refluxed with 1.5%dilute hydrochloric acid (75 ml) for 2 hours and cooled. To this wasadded a solution of benzylamine (13.25 ml) and concentrated hydrochloricacid (11 ml) in water (250 ml) followed by acetone dicarboxylic acid(19.2 g). The mixture was made up to 1 liter with water and the pHadjusted to 2.5. After stirring for 24 hours it was acidified withconcentrated hydrochloric acid and saturated with several portions ofdiethyl ether. The aqueous solution was then basified and extracted withdichloromethane (6×250 ml). The solution was evaporated and absorbed onalumina (100 g) and this was then placed in the thimble of a soxhletextraction apparatus. This was then continually extracted with ether for48 hours. Recrystallization gave the desired9-benzyl-9-aza-3-thiabicyclo[3,3,1]nonan-7-one as a white solid (8.3 g;30%).

DESCRIPTION 2 9-Benzyl-9-aza-3-oxabicyclo-(3,3,1)-nonan-7-one oxime (D3)##STR22##

The ketone (D1) from the previous reaction (0.96 g) was dissolved inethanol (60 ml) together with hydroxylamine hydrochloride (0.29 g) andpyridine (0.4 ml). This mixture was refluxed with stirring overnight,then poured into water and basified by the addition of solid potassiumcarbonate. The mixture was extracted with chloroform (4×250 ml), and thecombined organic extracts were dried (over sodium sulphate) andevaporated to yield the crude oxime (quantitative).

The following compound was prepared analogously:

9-benzyl-9-aza-3-thiabicyclo[3.3.1]nonan-7-one oxime. (D4) (crudequantitative yield) from (D2).

DESCRIPTION 3 7β-Amino-9-benzyl-9-aza-3-oxabicyclo(3,3,1)nonane (D5)##STR23##

The oxime (D3) from the previous reaction (2 g) was dissolved withstirring in amylalcohol (150 ml) and this was heated to 140° C. Sodium(6 g) was added in small pieces over a period of 40 minutes and whenaddition was complete, the solution was refluxed for a further 5 hours,then allowed to cool. The cold solution was poured into water and madestrongly acidic by the addition of hydrochloric acid. This was thenextracted with ethyl acetate (6×200 ml). The aqueous solution wasbasified with sodium hydroxide saturated with sodium chloride and thenextracted with chloroform (4×200 ml). Drying (over sodium sulphate)followed by evaporation of the solvent gave a quantitative yield of thecrude amine as a yellow oil which solidified on standing.

The following compound was prepared analogously:

7β-amino-9-benzyl-9-aza-3-thiabicyclo[3.3.1]nonane (D6) (98% yield) from(D4).

DESCRIPTION 4 7β-Acetamido-9-benzyl-9-aza-3-oxabicyclo(3,3,1)nonane (D7)##STR24##

The amine (D5) (19.5 g) from Description 3 was dissolved in 250 ml ofethanol together with a large excess of acetic anhydride. This mixturewas stirred at ambient temperature for 2 days. The solvent wasevaporated, aqueous sodium carbonate solution added and the solutionextracted with methylene chloride (3×200 ml). Drying (over magnesiumsulphate) followed by evaporation of the solvent gave the crude product(20.8 g, 92%).

DESCRIPTION 5 7β-Acetamido-9-aza-3-oxabicyclo(3,3,1)none (D8) ##STR25##

The product (D7) from Description 4 (5 g) was dissolved in 250 ml ofethanol and hydrogenated with 10% palladium/charcoal at atmosphericpressure and ambient temperature. The solution was filtered and solventevaporated to give a quantitative yield of the crude amine as an oilwhich solidified on standing.

DESCRIPTION 67β-Acetamido-9-(4-chlorobenzyl)-9-aza-3-oxabicyclo(3,3,1)nonane (D9)

The amine (1 g, 5.3 mmol) from Description 8 and p-chlorobenzyl chloride(0.87 g, 5.3 mmol) were dissolved in 40 ml of dry dimethylformamide andpotassium carbonate (2.2 g) added. The mixture was stirred at ambienttemperature for 2 days. The solvent was evaporated, water was added andthe solution extracted with methylene chloride (3×100 ml). Drying (overmagnesium sulphate) followed by evaporation of the solvent gave theproduct (1.33 g; 81%).

Similarly prepared were:

7β-Acetamido-9-(4-methoxybenzyl)-9-aza-3-oxabicyclo (3,3,1)nonane (D10)

7β-Acetamido-9-(3,4-dichlorobenzyl)-9-aza-3-oxabicyclo(3,3,1)nonane(D11)

7β-Acetamido-9-(3-trifluoromethylbenzyl)-9-aza-3-oxabicyclo(3,3,1)nonane(D12)

7β-Acetamido-9-(4-methylbenzyl)-9-aza-3-oxabicyclo (3,3,1)nonane (D13)

7β-Acetamido-9-(n-hexyl)-9-aza-3-oxabicyclo(3,3,1)nonane (D14)

7β-Acetamido-9-(2-thenyl)-9-aza-3-oxabicyclo(3,3,1)nonane (D15)

7β-Acetamido-9-(3-methylbutyl)-9-aza-3-oxabicyclo (3,3,1)nonane (D16)

7β-Acetamido-9-(cyclohexylmethyl)-9-aza-3-oxabicyclo (3,3,1)nonane (D17)

7β-Acetamido-9-(4-methylpentyl)-9-aza-3-oxabicyclo (3,3,1)nonane (D18)

7β-Acetamido-9-(n-heptyl)-9-aza-3-oxabicyclo(3,3,1)nonane (D19).

DESCRIPTION 77β-Amino-9-(4-chlorobenzyl)-9-aza-3-oxabicyclo(3,3,1)nonane (D18)

The product from Description 9 (1.33 g, 4.3 mmole) was dissolved in 20ml of ethanol and 20 ml of concentrated hydrochloric acid. The solutionwas refluxed for 8 hours, allowed to cool and the ethanol evaporated.The aqueous solution was washed with ethyl acetate, made basic withpotassium carbonate and extracted with methylene chloride (4×100 ml).Drying (over magnesium sulphate) followed by evaporation of the solventgave the amine as a yellow oil (0.63 g; 55%).

Similarly prepared were:

7β-Amino-9-(4-methoxybenzyl)-9-aza-3-oxabicyclo (3,3,1)nonane (D19)

7β-Amino-9-(3,4-dichlorobenzyl)-9-aza-3-oxabicyclo (3,3,1)nonane (D20)

7β-Amino-9-(3-trifluoromethylbenzyl)-9-aza-3-oxabicyclo(3,3,1)nonane(D21)

7β-Amino-9-(4-methylbenzyl)-9-aza-3-oxabicyclo(3,3,1)nonane (D22)

7β-Amino-9-(n-hexyl)-9-aza-3-oxabicyclo(3,3,1)nonane (D23)

7β-Amino-9-(2-thenyl)-9-aza-3-oxabicyclo(3,3,1)nonane (D24)

7β-Amino-9-(3-methylbutyl)-9-aza-3-oxabicyclo(3,3,1)nonane (D25)

7β-Amino-9-(cyclohexylmethyl)-9-aza-3-oxabicyclo(3,3,1)nonane (D26)

7β-Amino-9-(4-methylpentyl)-9-aza-3-oxabicyclo(3,3,1)nonane (D27)

7β-Amino-9-(n-heptyl)-9-aza-3-oxabicyclo(3,3,1)nonane (D28)

EXAMPLE 12-Methoxy-5-chloro-4-acetamido-N-[9-benzyl-9-aza-3-oxabicyclo(3,3,1)nonan-7β-yl]-benzamide(1) ##STR26##

2-Methoxy-5-chloro-4-acetamido-benzoic acid (2.47 g, 10.1 mmol) wasconverted to its acyl chloride by treatment with 20 ml thionyl chlorideat 40° C. for 4 hours, followed by removal of the excess thionylchloride. This was then dissolved in dry toluene (150 ml) and 4 ml oftriethylamine was added. A solution of the amine (2.14 g, 9.2 mmol) fromthe previous description in dry toluene (50 ml) was added and thesolution was allowed to sit at ambient temperature for 2 days.Chloroform (200 ml) was then added and the solution was washed withaqueous potassium carbonate solution, dried (over sodium sulphate) andevaporated. The oil was then redissolved in chloroform/ethyl acetate,filtered and chromatographed on 5% deactivated neutral alumina). Theyield of final material was 3.46 g (82%). m.pt. 186°-7° C. (fromchloroform/ethyl acetate).

The following compound was prepared analogously:

2-methoxy-5-chloro-4-acetamido-N-(9-benzyl-9-aza-3thiabicyclo[3.3.1]nonan-7β-yl)benzamide(3) (52% yield, mp. 179°-181° C.).

EXAMPLE 22-Methoxy-5-chloro-4-amino-N-[9-benzyl-9-aza-3-oxabicyclo(3,3,1)nonan-7.beta.-yl]-benzamide(2) ##STR27##

The benzamide of Example 1 (1.85 g, 4 mmol) was dissolved in 50 mlethanol containing 3 ml water and 2 g potassium hydroxide. This wasrefluxed on a steam bath for 11/2 hours, poured into water and saturatedwith sodium chloride. The aqueous solution was extracted with chloroform(6×200 ml) and the combined organic layers were dried (sodium sulphate)filtered and evaporated to yield the crude desired benzamide, (1.5 g,90%). This was recrystallised from chloroform/ethanol/ethyl acetate toyield 1.1 g pale yellow crystals. m.pt. 255°-7° C.

The following compound was prepared analogously:

2-methoxy-5-chloro-4-amino-N-(9-benzyl-9-aza-3-thiabicyclo[3.3.1]nonan-7.beta.-yl)benzamide(4) (66% yield, mp 263°-4° C.) from (3).

EXAMPLE 3 2-Methoxy-5-methylsulphonyl-N-[9-benzyl-9-aza-3-thiabicyclo(3,3,1)nonan-7β-yl]benzamide (5)

2-methoxy-5-methylsulphonylbenzoic acid (1.47 g) was dissolved indimethylformamide containing triethylamine (0.65 g) and to this wasadded ethyl chloroformate (0.7 g). The mixture was stirred for 2 hoursthen 7β-amino-9-benzyl-9-aza-3-thiabicyclo(3,3,1)nonane (D6) (1.44 g)was added. These were stirred together for 48 hours and then thedimethylformamide was stripped off in vacuo and the mixture poured intoaqueous potassium carbonate solution. This was extracted withchloroform, dried (sodium sulphate) filtered and evaporated to give thecrude product (2.5 g). Purification by chromatography on deactivatedneutral alumina gave the desired2-methoxy-5-methylsulphonyl-N-[9-benzyl-9-aza-3-thiabicyclo(3,3,1)nonan-7.beta.-yl]benzamide(1.87 g; 70%; mp. 197°-9° C.

EXAMPLE 42,3-Dimethoxyj-[N-(9-benzyl-9-aza-3-oxabicyclo(3,3,1)nonan-7β-yl)]benzamide(6)

2,3-Dimethoxybenzoic acid (1.18 g; 6.5 mmol) was converted to its acylchloride by treatment with 20 ml thionyl chloride at 40° C. for 4 hours,followed by removal of the excess thionyl chloride. A solution of theamine (1.5 g, 6.5 mmol) (D7) in dry toluene (50 ml) was added, followedby 2 ml of triethylamine, and the solution stirred at ambienttemperature for 24 hours. The solvent was evaporated, aqueous sodiumcarbonate solution added and the solution extracted with methylenechloride (3×50 ml). The combined organic extracts were dried (overmagnesium sulphate) and evaporated. The oil was then chromatographed onsilica gel. The yield of final material was 1.1 g (43%) mp. 140°-2° C.(from ethyl acetate/ether).

Similarly prepared was:

2,4,5-Trimethoxy-[N-(9-benzyl-9-aza-Lb3-oxabicyclo(3,3,1)nonan-7β-yl)benzamide. Yield 0.4 g; (20%) mp. 125°-8°C.

EXAMPLE 52-Methoxy-5-chloro-4-acetamido-[N-(9-(4'-chlorobenzyl)9-aza-3-oxabicyclo(3,3,1)nonan-7β-yl)]benzamide(8)

2-Methoxy-5-chloro-4-acetamidobenzoic acid (0.73 g, 3.0 mmol) wasconverted to its acyl chloride by treatment with 20 ml thionyl chlorideat 40° C. for 4 hours, followed by removal of the excess thionylchloride. A solution of the amine (0.81 g, 3.0 mmol) (D7) in dry toluene(50 ml) was added, followed by 2 ml of triethylamine, and the solutionwas stirred at ambient temperature for 24 hours. The solvent wasevaporated, aqueous sodium carbonate solution added and the solutionextracted with methyline chloride (3×50 ml). Drying (over magnesiumsulphate) followed by evaporation of the solvent gave an oil which waschromatographed on silica gel. The yield of final material was 1.0 g(68%).

Similarly prepared were:

2-Methoxy-5-chloro-4-acetamido-[N-(9-(3',4'-dichlorobenzyl)-9-aza-3-oxabicyclo[3.3.1]nonan-7β-yl)]benzamide(9)

2-Methoxy-5-chloro-4-acetamido-[N-(9-(3'-trifluoromethylbenzyl)-9-aza-3-oxabicyclo[3.3.1]nonan-7β-yl)]benzamide(10)

2-Methoxy-5-chloro-4-acetamido-[N-(9-(4'-methylbenzyl)9-aza-3-oxabicyclo[3.3.1]nonan-7β-yl)]benzamide(11)

2-Methoxy-5-chloro-4-acetamido-[N-(9-(n-hexyl)-9-aza-3-oxabicyclo[3.3.1]nonan-7β-yl)]benzamide(12)

2-Methoxy-5-chloro-4-acetamido-[N-(9-(2'-thenyl)-9-aza-3-oxabicyclo[3.3.1]nonan-7β-yl)]benzamide(13)

2-Methoxy-5-chloro-4-acetaido-[N-(9-(3'-methylbutyl)9-aza-3-oxabicyclo[3.3.1]nonan-7β-yl)]benzamide(14)

2-Methoxy-5-chloro-4-acetamido-[N-(9-(cyclohexylmethyl)9-aza-3-oxabicyclo[3.3.1]nonan-7β-yl)]benzamide(15)

2-Methoxy-5-chloro-4-acetamido-[N-(9-(4-methylpentyl)9-aza-3-oxabicyclo[3.3.1]nonan-7β-yl)]benzamide(16)

2-Methoxy-5-chloro-4-acetamido-[N-(9-(n-heptyl)9-aza-3-oxabicyclo[3.3.1]nonan-7β-yl)]benzamide(7)

EXAMPLE 62-Methoxy-5-chloro-4-amino-[N-(9-(4-chlorobenzyl)-9-aza-3-oxabicyclo(3,3,1)nonan-7β-yl)]benzamide(18)

The benzamide (8) (1.0 g, 2.0 mmol) was dissolved in 50 ml ethanolcontaining 3 ml water and 1 g potassium hydroxide. This was refluxed for2 hours, allowed to cool and the solvent evaporated. Aqueous sodiumcarbonate solution was added and the solution extracted with methlenechloride (4×100 ml). Drying (over magnesium sulphate) followed byevaporation of the solvent gave the crude desired benzamide (0.72 g).This was recrystallised from ethanol to yield 0.57 g (63%) pale yellowcrystals mpt 240°-2° C.

Similarly prepared were:

2-Methoxy-5-chloro-4-amino-[N-(9-(4-methoxybenzyl)9-aza-3-oxabicyclo(3,3,1)nonan-7β-yl)]benzamide(19)

Yield: 0.3 g, (47%) mp. 215°-17° C.

2-Methoxy-5-chloro-4-amino-[N-(9-(3,4-dichlorobenzyl)-9-aza-3-oxabicyclo(3,3,1)nonan-7β-yl)]benzamide(20)

Yield: 0.4 g, (50%) mp. 221°-3° C.

2-Methoxy-5-chloro-4-amino-[N-(9-(3-trifluoromethylbenzyl)-9-aza-3-oxabicyclo(3,3,1)nonan-7β-yl)]benzamide(21)

Yield: 0.6 g, (44%) mp. 217°-9° C.

2-Methoxy-5-chloro-4-amino-[N-(9-(4-methylbenzyl)-9-aza-3-oxabicyclo(3,3,1)nonan-7β-yl)]benzamide(22)

Yield: 0.6 g, (44%) mp. 223°-5° C.

2-Methoxy-5-chloro-4-amino[N-(9-(n-hexyl)-9-aza-3-oxabicyclo(3,3,1)nonan-7.beta.-yl)]benzamide(23)

Yield: 0.4 g, (41%) mp. 173°-5° C.

2-Methoxy-5-chloro-4-amino-[N-(9-(2-thenyl)-9-aza-3-oxabicyclo(3,3,1)nonan-7β-yl)]benzamide(24)

Yield: 0.6 g, (42%) mp. 228°-30° C.

2-Methoxy-5-chloro-4-amino-[N-(9-(3-methylbutyl)-9-aza-3-oxabicyclo(3,3,1)nonan-7β-yl)]benzamide(25)

Yield: 0.3 g, (33%) mp. 231°-2° C.

2-Methoxy-5-chloro-4-amino-[N-(9-cyclohexylmethyl)-9-aza-3-oxabicyclo(3,3,1)nonan-7β-yl)]benzamide(26)

Yield: 0.3 g, (55%) as a foam.

2-Methoxy-5-chloro-4-amino-[N-(4-methylpentyl)-9-aza-3-oxabicyclo(3,3,1)nonan-7β-yl)]benzamide(27)

2-Methoxy-5-chloro-4-amino-[N-(n-heptyl)-9-aza-3-oxabicyclo(3,3,1)nonan-7.beta.-yl)]benzamide(28).

PHARMACOLOGICAL DATA I. Anti-emetic activity in the dog

Compounds were administered subcutaneously 30 minutes prior toadministration of a standard dose of apomorphine HCl (0.1 mg/kgsubcutaneously) and the vomiting response compared to that obtained whenthe same animals were dosed with apomorphine HCl and vehicle only.

The following results were obtained:

    ______________________________________                                        Compound Number ED.sub.50 (mg/kg s.c.)                                        ______________________________________                                        2               0.005                                                         5               0.1                                                           ______________________________________                                    

II. Dopamine Receptor Blocking Activity in the Central Nervous System

Compounds were tested for inhibition of apomorphine induced climbing inthe mouse. The test is based on that described by Protais, P.,Constantin, J. and Schwartz J. C. (1976), Psychopharmacology, 50, 1-6.

Apomorphine 1 mg/kg s.c. induces mice to climb the wall of a wire cage(inverted food hopper-11×7.5×18 cm high). Mice acclimatised in theirhome cages in groups of 5 are placed under the hoppers immediately afterthe injection of apomorphine 1 mg/kg s.c. At 10,20 and 30 minutes afterinjection climbing behaviour is scored. The mice are observed for 30seconds and scored according to the position they spend the majority oftime in, score 0--four paws on floor of cage; score 1--four paws only onwalls; score 2--all paws on wall of cage. The scores at all 3 times andfor each mouse are summed and mice drug treated orally compared to micereceiving apomorphine only. A saline only treated group is also includedand any score, generally <5% of maximum taken into account.

The following results were obtained:

    ______________________________________                                        Compound Number                                                                              Active Dose (mg/kg)                                            ______________________________________                                                       p.o.                                                           1              2                                                              2              1                                                              3              ED.sub.50 -1.5                                                 4              ED.sub.50 -3.7                                                 5                50 (s.c.)                                                    6              2                                                              7              10                                                             18             10                                                             19             10                                                             20             10                                                             21             50                                                             22             10                                                             23             10                                                             24             10                                                             25             10                                                             26             10                                                             ______________________________________                                    

It should be noted that these doses (except where ED₅₀ 's are quoted)are not necessarily the lowest active doses.

III. Gastric Motility Testing in the rat

The compounds were tested for ability to reverse the inhibitory effectof 6,7-ADTN on gastric motility as recorded by an open tipped catheterin the conscious chronic gastric fistula rat. Administration of 1 mg/kgs.c. of 6,7-ADTN reduced basal gastric motor activity and this wasreversed by the administration of the compound administered 10 minutesafter the 6,7-ADTN. Control injections did not reverse the inhibition.For subcutaneous testing the compound was dissolved in water by theaddition of tartaric acid (1/2 mole per mole of compound).

Compounds 2 and 5 both reversed the action of 6,7-ADTN at 1 mg/kg s.c.

What we claim is:
 1. A compound of the formula (I) or a pharmaceuticallyacceptable salt thereof: ##STR28## characterised in that: X is oxygen orsulphur;R₁ is a C₁₋₆ alkoxy or C₁₋₆ alkylthio group; R₂ and R₃ are thesame or different and are hydrogen, halogen, CF₃, C₁₋₇ acyl, C₁₋₇acylamino or amino, aminocarbonyl or aminosulphonyl optionallysubstituted by one or two C₁₋₆ alkyl groups, C₁₋₆ alkylsulphonyl, C₁₋₆alkylsulphinyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, hydroxy or nitro or R₁ andR₂ taken together are methylenedioxy or ethylenedioxy in which case R₃is any one of the groups given for R₂ and R₃ above; R₄ is C₁₋₇ alkyl ora group --(CH₂)_(s) R₅ where s is 0 to 2 and R₅ is a C₃₋₈ cycloalkylgroup, or a group --(CH₂)_(t) R₆ where t is 1 or 2 and R₆ is a phenylgroup optionally substituted by one or two substituents selected fromC₁₋₆ alkyl, C₁₋₄ alkoxy, trifluoromethyl and halogen, or a thienylgroup; and n is 0 to 2;and there are at least two carbon atoms betweenthe benzamide and heterogranatane ring nitrogen atoms.
 2. A compoundaccording to claim 1 or a pharmaceutically acceptable salt thereofcharacterised in that:R₁ is C₁₋₆ alkoxy; R₂ and R₃ are the same ordifferent and are hydrogen, halogen, trifluoromethyl, C₁₋₇ acyl, C₁₋₇acylamino, or amino, aminocarbonyl or aminosulphonyl optionallysubstituted by one or two C₁₋₆ alkyl groups; C₁₋₆ alkylsulphonyl, C₁₋₆alkylsulphinyl or nitro; or R₁ and R₂ taken together are methylenedioxyor ethylenedioxy, in which case R₃ is any one of the groups given for R₁and R₂ above; R₄ is C₁₋₇ alkyl or a group --(CH₂)_(s) R₅ where s is 0 to2 and R₅ is a C₃₋₈ cycloalkyl group, or a group --(CH₂)_(t) R₆ where tis 1 or 2 and R₆ is a phenyl group optionally substituted by one or twosubstituents selected from C₁₋₆ alkyl, C₁₋₆ alkoxy, trifluoromethyl andhalogen; X is oxygen or sulphur; n is 0, 1 or 2; and there are at leasttwo carbon atoms between the benzamide and side-chain nitrogen atoms. 3.A compound according to claim 1 having the formula (IV) or apharmaceutically acceptable salt thereof: ##STR29## characterised inthat: X and R₄ are as defined in claim 1, and R₉ in hydrogen or C₁₋₇alkanoyl.
 4. A compound according to claim 3 having the formula (V) or apharmaceutically acceptable salt thereof: ##STR30## wherein: R¹ ₄ isC₅₋₇ alkyl, and R₉ is as defined in claim
 3. 5.2-Methoxy-5-chloro-4-amino-N-(9-n-hexyl-9-aza-3-oxabicyclo[3.3.1]non-7β-yl)benzamide,2-Methoxy-5-chloro-4-amino-N-[9-(3'-methylbutyl)-9-aza-3-oxabicyclo[3.3.1]non-7β-yl)benzamide,2-Methoxy-5-chloro-4-acetamido-N-(9-n-hexyl-9-aza-3-oxabicyclo[3.3.1]non-7.beta.-yl)benzamide,or2-Methoxy-5-chloro-4-amino-N-[9-(3'-methylbutyl)-9-aza-3-oxabicyclo[3.3.1]non-7β-yl)benzamide,or a pharmaceutically acceptable salt thereof.
 6. A compound accordingto claim 3 having the formula (VI): ##STR31## wherein: R² ₄ is a group--(CH₂)_(t) R¹ wherein t is 1 or 2 and R¹ ₆ is optionally substitutedphenyl as defined in formula (I); cyclohexylmethyl; or 2-thienylmethyl,and R₉ is as defined in claim
 3. 7.2-Methoxy-5-chloro-4-amino-N-(9-benzyl-9-aza-3-oxabicyclo[3.3.1]non-7β-yl)benzamide,2-Methoxy-5-chloro-4-amino-N-[9-(4'-chlorobenzyl)-9-aza-3-oxabicyclo[3.3.1]non-7β-yl]benzamide,2-Methoxy-5-chloro-4-amino-N-[9-(3',4'-dichlorobenzyl)-9-aza-3-oxabicyclo[3.3.1]non-7β-yl]benzamide,2-Methoxy-5-chloro-4-amino-N-[9-(3'-trifluoromethylbenzyl)-9-aza-3-oxabicyclo[3.3.1]non-7β-yl]benzamide,2-Methoxy-5-chloro-4-amino-N-[9-(4'-methylbenzyl)-9-aza-3-oxabicyclo[3.3.1]non-7β-yl]benzamide,2-Methoxy-5-chloro-4-amino-N-[9-(2'-thenyl)-9-aza-3-oxabicyclo[3.3.1]non-7.beta.-yl]benzamide,2-Methoxy-5-chloro-4-amino-N-[9-(cyclohexylmethyl)-9-aza-3-oxabicyclo[3.3.1]non-7β-yl]benzamide,2-Methoxy-5-chloro-4-acetamido-N-(9-benzyl-9-aza-3-oxabicyclo[3.3.1]non-7.beta.-yl)benzamide,2-Methoxy-5-chloro-4-acetamido-N-[9-(4'-chlorobenzyl)-9-aza-3-oxabicyclo[3.3.1]non-7β-yl]benzamide,2-Methoxy-5-chloro-4-acetamido-N-[9-(3',4'-dichlorobenzyl)-9-aza-3-oxabicyclo[3.3.1]non-7β-yl]benzamide,2-Methoxy-5-chloro-4-acetamido-N-[9-(3'-trifluoromethylbenzyl)-9-aza-3-oxabicyclo[3.3.1]non-7β-yl]benzamide,2-Methoxy-5-chloro-4-acetamido-N-[9-(4'-methylbenzyl)-9-aza-3-oxabicyclo[3.3.1]non-7β-yl]benzamide,2-Methoxy-5-chloro-4-acetamido-N-[9-(2'-thenyl)-9-aza-3-oxabicyclo[3.3.1]non-7β-yl]benzamide,or2-Methoxy-5-chloro-4-acetamido-[9-(cyclohexylmethyl)-9-aza-3-oxabicyclo[3.3.1]non-7β-yl]benzamide,or a pharmaceutically acceptable salt thereof.
 8. A compound accordingto claim 1 having the formula (IX) or a pharmaceutically acceptable saltthereof: ##STR32## wherein: R¹ ₁ is C₁₋₆ alkoxy;R¹ ₂ and R¹ ₃ are thesame or different and are hydrogen, aminosulphonyl optionallysubstituted by one or two C₁₋₆ alkyl groups, C₁₋₆ alkylsulphonyl, C₁₋₆alkylsulphinyl, C₁₋₆ alkoxy or hydroxy or R¹ ₁ and R¹ ₂ taken togetherare methylenedioxy or ethylenedioxy, in which case R¹ ₃ is any one ofthe groups given above for R¹ ₁ and R¹ ₂ ; and X is oxygen or sulphurand R² ₄ is a group --(CH₂)_(t) R¹ wherein t is 1 or 2 and R¹ ₆ isoptionally substituted phenyl as defined with respect to formula (I),cyclohexylmethyl or 2-thienylmethyl. 9.2-Methoxy-5-methylsulphonyl-N-[9-benzyl-9-aza-3-thiabicyclo[3.3.1]non-7β-yl]benzamide,or a pharmaceutically acceptable salt thereof.
 10. A compound accordingto claim 8 having the formula (XI) or a pharmaceutically acceptable saltthereof: ##STR33## wherein: X, R¹ ₁ and R² ₄ are as defined in claim8.R² ₂ and R³ ₃ are the same or different and are C₁₋₆ alkoxy orhydrogen; or R¹ ₁ and R² ₂ taken together are methylenedioxy orethylenedioxy, in which case R³ ₃ is any one of the groups given abovefor R² ₂ and R³ ₃. 11.2,3-Dimethoxy-N-(9-benzyl-9-aza-3-oxabicyclo[3.2.1]non-7β-yl)benzamide,or2,4,5-Trimethoxy-N-(9-butyl-9-aza-3-oxabicyclo[3.2.1]non-7β-yl)benzamide,or a pharmaceutically acceptable salt thereof.
 12. A pharmaceuticalcomposition having dopamine antagonist activity comprising an effectiveamount of a compound according to claim 1 or a hydrate or apharmaceutically acceptable salt thereof, together with apharmaceutically acceptable carrier.
 13. A method of treatment ofmaladies in humans comprising the administration of a composition ofclaim 12 containing an effective amount of a compound of formula (I) ora pharmaceutically acceptable salt or a hydrate thereof.